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Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease.

Abstract : Neurodegenerative diseases are characterized by the presence of filamentous aggregates of proteins. We previously established that lithostathine is a protein overexpressed in the pre-clinical stages of Alzheimer's disease. Furthermore, it is present in the pathognomonic lesions associated with Alzheimer's disease. After self-proteolysis, the N-terminally truncated form of lithostathine leads to the formation of fibrillar aggregates. Here we observed using atomic force microscopy that these aggregates consisted of a network of protofibrils, each of which had a twisted appearance. Electron microscopy and image analysis showed that this twisted protofibril has a quadruple helical structure. Three-dimensional X-ray structural data and the results of biochemical experiments showed that when forming a protofibril, lithostathine was first assembled via lateral hydrophobic interactions into a tetramer. Each tetramer then linked up with another tetramer as the result of longitudinal electrostatic interactions. All these results were used to build a structural model for the lithostathine protofibril called the quadruple-helical filament (QHF-litho). In conclusion, lithostathine strongly resembles the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.
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Contributor : Jean-Michel Verdier Connect in order to contact the contributor
Submitted on : Monday, May 7, 2007 - 6:01:00 PM
Last modification on : Friday, January 14, 2022 - 3:03:17 AM
Long-term archiving on: : Tuesday, April 6, 2010 - 11:19:26 PM




Catherine Grégoire, Sergio Marco, Jean Thimonier, Laure Duplan, Emmanuelle Laurine, et al.. Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease.. EMBO Journal, EMBO Press, 2001, 20 (13), pp.3313-21. ⟨10.1093/emboj/20.13.3313⟩. ⟨inserm-00144804⟩



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